Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: RAD50

Red List (low evidence)

Comment on list classification: New gene added by Boaz Palterer. Of the three total patients reported to date with biallelic variants in this gene, only one exhibited bone marrow failure and immunodeficiency (PMID: 33378670). Therefore rating Red on this panel until further cases are reported which indicate that RAD50 variants contribute to immunodeficiency

Created: 1 Apr 2021, 3:09 p.m. | Last Modified: 1 Apr 2021, 3:09 p.m.

Panel Version: 2.407

- PMID:33378670 - single patient described with bone marrow failure, immunodeficiency and developmental defects, who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.

Of note, two other unrelated individuals have also been reported with biallelic RAD50 variants and a similar phenotype (MIM# 613078) - however, neither of these cases presented immunodeficiency (PMIDs: 19409520 and 32212377)

Created: 1 Apr 2021, 1:54 p.m. | Last Modified: 1 Apr 2021, 1:54 p.m.

Panel Version: 2.406

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nijmegen breakage syndrome-like disorder, OMIM:613078

Publications

• 33378670

Red List (low evidence)

Chansel-Da Cruz et al. identified a single patient with bone marrow failure, immunodeficiency and developmental defect caused by compound heterozygous mutations in RAD50. The first mutations generate a null allele, the second is hypothesized to be hypomorphic because of the loss of a single amino acid residue in the coiled-coil domain of RAD50.
Sources: Literature

Created: 24 Feb 2021, 10:16 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
bone marrow failure; immunodeficiency; developmental defect

Publications

• 33378670